Revisiting the ‘Chemotropic Theory’ of neural wiring

Division of Brain Function / Hirata Group

Netrin-1 Derived from the Ventricular Zone, but not the Floor Plate, Directs Hindbrain Commissural Axons to the Ventral Midline

Kenta Yamauchi, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Heiko Lickert, Takahiko Kawasaki, Fujio Murakami, and Tatsumi Hirata

Scientific Reports, DOI:10.1038/s41598-017-12269-8

In this study, we have provided evidence that Netrin-1 (Ntn1) from the ventricular zone (VZ), but not the floor plate (FP), a glial structure occupying the ventral midline (VM), guides hindbrain commissural axon (CA) to the VM. Our results are incompatible with the prevailing view that Ntn1 is a chemoattractant for CAs, rather suggest a novel mechanism that VZ-derived Ntn1 directs CAs to the VM by its local actions.

More than a century ago, based on his observations of CA growth towards the VM, Ramón y Cajal proposed the ‘chemotropic theory’, attraction of growth cones by a long-range diffusible cue emanating from their targets. Ntn1 emanating from the VM has been assumed as the chemoattractant. Consistent with this view, Ntn1 is expressed in the VM and can attract CAs at a distance in vitro. However, Ntn1 is expressed in the vicinity of the CA path, the VZ, in addition to the FP, raising an alternative possibility that Ntn1 of extra-FP origin directs CAs to the VM. To test this possibility, we generated Ntn1 FP conditional mutant (Ntn1FP-Ko) and VZ conditional mutant mice (Ntn1VZ-Ko). If Ntn1 acts CAs as a long-range diffusible chemoattractant, CA guidance to the VM should be disrupted in Ntn1FP-Ko mice. Contrary to the prediction, deletion of Ntn1 from the VZ highly disrupted CA guidance to the VM, whereas deletion of Ntn1 from the FP had little impact on it (Figure). Our results fail to support the chemotropic theory proposed by Ramón y Cajal, and rather suggest that local actions of Ntn1 from the VZ direct CAs to the VM.


Hindbrain CA growth in Ntn1FP-Ko and Ntn1VZ-Ko mice. Deletion of Ntn1 from the VZ highly disrupts CA guidance to the VM (right), whereas deletion of Ntn1 from the FP has little impact on it (left, arrowheads). CA is labeled with a fluorescent lipophlic dye, DiI.